The following are 10 points to remember about proprotein convertase subtilism/kexin 9 (PCSK9) inhibitors in the cardiovascular field:

Clearance of circulating low-density lipoprotein cholesterol (LDL-C) results primarily from binding to hepatocyte LDL-receptors (LDL-Rs) that undergo endocytosis with the LDL-R recirculated back to the cell surface about 150 times. The binding of circulating PCSK9 to LDL-R is responsible for stopping recirculation of LDL-R to the membrane by enhancing the degradation in the lysosome.

Gain-of-function mutations in PCSK9 reduce the LDL-Rs and are one of the genetic causes of familial hypercholesterolemia. The finding that loss-of-function in PCSK9 results in a modest lowering of LDL-C over a lifetime and reduces coronary heart disease triggered the development of the PCSK9 inhibitors.

Among the many PCSK9 inhibitors developed to lower LDL-C, parenteral monoclonal antibodies (MoAbs) have been the most successful. The most advanced in late-stage clinical trials are alirocumab (Regeneron Pharmaceutical Inc.) and evolocumab (Amgen Inc.).

A dose-dependent reduction in LDL-C (up to 70%) occurred at between 4 and 14 days with a 2 to 8+ week delay in return to baseline with each of the MoAbs.

Alirocomab dosing is 150 mg subcutaneous (SC) every 2 weeks and evolocumab 140 mg SC every 2 weeks or 420 mg every 4 weeks. In phase 2, 12-week placebo-controlled studies, each reduced LDL-C in the majority of patients 60-70% (75-85 mg/dl) at trough and >90% (>100 mg/dl) at peak. Over 70% of patients with hyperlipidemia on statins were able to achieve an LDL-C <70 mg/dl. Two other MoAbs in phase 2 trials were less effective.

LDL-C was lowered by both highly effective MoAbs to the same degree regardless of whether subjects were also on lipid-lowering agents (statins or ezetamibe) or had heterozygous familial hypercholesterolemia. There was no difference of response by age, sex, diabetes, or cardiovascular risk. The reduction at 1 year of treatment was similar to that in the 12-week studies.

Evolocumab reduced LDL-C in homozygous familial hypercholesterolemia patients who had between 2% and 25% of LDL-R activity, but not in those with nonfunctioning LDL-Rs. Both MoAbs significantly reduced apolipoprotein (apo) B, total cholesterol, triglycerides, non–high-density lipoprotein (HDL), and lipoprotein (a), but not HDL, apo A, or C-reactive protein.

Placebo-controlled trials in statin-intolerant patients showed no excess in myalgias or other adverse events such has viral infections, insulin resistance, or glucose intolerance.

In phase 3 placebo-controlled trials in patients on maximally tolerated statin, both MoAbs reduced the LDL-C about 2x that of ezetamibe. In patients on high-intensity statins and an LDL-C >150 mg/dl, evolocumab reduced mean LDL-C by 63-75%, and results were similar on moderate statin dosing.

Given the finding of a 22% reduction in major cardiovascular events for each 1 mmol/L (37.8 mg/dl) reduction of LDL-C in cholesterol-lowering trials that was constant across a broad range of LDL-C values, the LDL-C reduction from MoAbs is expected to result in about a 40% reduction in major cardiovascular events. Ongoing phase 3 trials in persons at high risk are powered to examine the effect of MoAbs on cardiovascular events. Completion is projected for late 2017.